Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multi-center trial (Study 1), 1589 kidney transplant patients received tacrolimus (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine regimens (Group A, n=390 and Group B, n=399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The study was conducted outside the United States; the study population was 93% Caucasian. In this study, mortality at 12 months in patients receiving Tacrolimus/MMF was similar (2.7%) compared to patients receiving cyclosporine/MMF (3.3% and 1.8%) or sirolimus/MMF (3.0%). Patients in the tacrolimus group exhibited higher estimated creatinine clearance rates (eCLcr) using the Cockcroft-Gault formula (Table 1) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up (Table 2) in comparison to each of the other three groups. Patients randomized to tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen (see ADVERSE REACTIONS ).

Table 1: Estimated Creatinine Clearance at 12 Months in Study 1

Group eCLcr [mL/min] at Month 12 a 
N MEAN SD MEDIAN Treatment Difference with Group C (99.2% CI b)
(A) CsA/MMF/CS  390 56.5 25.8 56.9 -8.6 (-13.7, -3.7)
(B) CsA/MMF/CS/Daclizumab 399 58.9 25.6 60.9 -6.2 (-11.2, -1.2)
(C) Tac/MMF/CS/Daclizumab  401 65.1 27.4 66.2 -
(D) Siro/MMF/CS/Daclizumab  399 56.2 27.4 57.3 -8.9 (-14.1, -3.9)
Total 1589 59.2 26.8 60.5

Key: CsA=Cyclosporine, CS=Corticosteroids, Tac=Tacrolimus, Siro=Sirolimus

a)    All death/graft loss (n=41, 27, 23 and 42 in Groups A, B, C and D) and patients whose last recorded creatinine values were prior to month 3 visit (n=10, 9, 7 and 9 in Groups A, B, C and D) were inputed with GFR of 10 mL/min; a subject's last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n=11, 12, 15 and 19 for Groups A, B, C and D). Weight was also imputed in the calculation of estimated GFR, if missing.

b)    Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.

Table 2: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months in  Study 1

  A
N=390 B
N=399 C
N=401 D
N=399
Overall Failure Components of efficacy failure  141 (36.2%)  126 (31.6%)  82 (20.4%)  185 (46.4%) 
BPAR  113 (29.0%) 106 (26.6%) 60 (15.0%) 152 (38.1%)
Graft loss excluding death  28 (7.2%) 20 (5.0%)  12 (3.0%) 30 (7.5%)
Mortality 13 (3.3%) 7 (1.8%) 11 (2.7%) 12 (3.0%)
 Lost to follow-up  5 (1.3%) 7 (1.8%) 5 (1.3%)  6 (1.5%)
Treatment Difference of efficacy failure compared to Group C (99.2% CI a)   15.8% (7.1%, 24.3%)  11.2% (2.7%, 19.5%)  -  26.0% (17.2%, 34.7%)

Group A=CsA/MMF/CS,  B=CsA/MMF/CS/Daclizumab,  C=Tac/MMF/CS/Daclizumab, and D=Siro/MMF/CS/Daclizumab

a) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.

The protocol-specified target tacrolimus t